Malaria is an infectious disease that causes severe morbidity and mortality with an estimated 300-500 million cases worldwide and more than 1 million deaths annually in sub-Saharan Africa alone and affected patients are of all age groups. The disease is caused by protozoan parasites of the genus Plasmodium, transmitted by mosquitoes. The most serious forms of malaria are caused by Plasmodium falciparum and Plasmodium vivax, but other species (e.g., Plasmodium ovale, Plasmodium malariae, and Plasmodium knowles[iota]) can also infect humans.
The commonly used drugs are, for example Atovaquone, Proguanil as hydrochloride salt, Primaquine, for the treatment/prophylaxis of malaria.
Atovaquone (Formula I), chemical name being trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, is a hydroxy-1,4-naphthoquinone, an analog of Ubiquinone, with antipneumocystic and anti-malarial activity. It has previously been disclosed, for example, in European Patent No. 1,23,238 that Atovaquone is active (in animals and in vitro) against Pneumocystis (carinii) jirovecii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii.

Proguanil (Formula II) as hydrochloride salt is a well-known drug mainly for prophylaxis, but not commonly used for treatment of malaria. Cycloguanil is a metabolite of Proguanil and its formation in vivo has been thought to be responsible for the antimalarial activity of Proguanil. It is one of the safest antimalarial drugs and may be given to young children and pregnant women.

Control of malaria has been hampered by the spread of drug resistance in both the Plasmodium parasites and the Anopheles insect vector, and by the lack of an efficacious vaccine (Moorthy, V. S. et al., 2004. Lancet 363:150-156). In order to combat drug resistance and to improve antimalarial chemotherapy, a combination of antimalarials is used, either simultaneously or sequentially. One such combination of Atovaquone and Proguanil as hydrochloride salt (trade name: Malarone) for the treatment of malaria has previously been disclosed in WO9412164, U.S. Pat. No. 6,413,993, WO2009001367, and WO2009042960.
Atovaquone is a highly lipophilic compound with very poor solubility & bioavailability, classified according to the biopharmaceutical classification system (BCS) as class II drug. U.S. Pat. No. 6,018,080 & U.S. Pat. No. 6,649,659 mentions that efficacy of Atovaquone as a therapeutic agent is limited because of its poor bio-availability due to poor solubility of the crystals in common organic/aqueous solvents. It is noted that the label information of Malarone from US FDA shows that absolute bioavailability of the tablet formulation of Atovaquone is only 23%, meaning almost 67% of Atovaquone is not absorbed in the body.
According to European and Indian Pharmacopeia, Proguanil hydrochloride exhibits poor solubility in common organic/aqueous solvents and thus a mere physical admixture composition of these two molecules, like in Malarone, does not alter individual properties and thus the above existing combination exhibits poor solubility and hence less bio-availability.
Therefore, there is a need in the art to improve physico-chemical properties of Atovaquone-Proguanil combination, thereby greatly influencing pharmacokinetic effects, bioavailability and therapeutic efficacy. This forms the object of the present invention.